Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by multiple cellular and molecular dysfunctions of the innate and adaptive immunity. Cytotoxic function of NK cells is compromised in patients with SLE. Herein, we characterized the phenotypic alterations of SLE NK cells in a comprehensive manner to further delineate the mechanisms underlying the cytotoxic dysfunction of SLE NK cells and identify novel potential therapeutic targets. Therefore, we examined PBMC from SLE patients and matched healthy controls by single-cell mass cytometry to assess the phenotype of NK cells. In addition, we evaluated the cell function of NK cells (degranulation and cytokine production) and the killing of B cell subpopulations in a B cell-NK cell in vitro co-culture model. We found that SLE NK cells expressed higher levels of CD38 and were not able to adequately upregulate SLAMF1 and SLAMF7 following activation. In addition, ligation of SLAMF7 with elotuzumab or of CD38 with daratumumab on SLE NK cells enhanced degranulation of both healthy and SLE NK cells and primed them to kill circulating plasma cells in an in vitro co-culture system. Overall, our data indicated that dysregulated expression of CD38, SLAMF1 and SLAMF7 on SLE NK cells is associated with an altered interplay between SLE NK cells and plasma cells, thus suggesting their contribution to the accumulation of (auto)antibody producing cells. Accordingly, targeting SLAMF7 and CD38 may represent novel therapeutic approaches in SLE by enhancing NK cell function and promoting elimination of circulating plasma cell.

Innate lymphoid cells (ILC) are a heterogeneous group of immune cells characterized by lymphoid morphology and cytokine profile similar to T cells but which do not express clonally distributed diverse antigen receptors. These particular cells express transcription factors and cytokines reflecting their similarities to T helper (Th)1, Th2, and Th17 cells and are therefore referred to as ILC1, ILC2, and ILC3. Other members of the ILC subsets include lymphoid tissue inducer (LTi) and regulatory ILC (ILCreg). Natural killer (NK) cells share a common progenitor with ILC and also exhibit a lymphoid phenotype without antigen specificity. ILC are found in low numbers in peripheral blood but are much more abundant at barrier sites such as the skin, liver, airways, lymph nodes, and the gastrointestinal tract. They play an important role in innate immunity due to their capacity to respond rapidly to pathogens through the production of cytokines. Recent evidence has shown that ILC also play a key role in autoimmunity, as alterations in their number or function have been identified in systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Here, we review recent advances in the understanding of the role of ILC in the pathogenesis of autoimmune diseases, with particular emphasis on their role as a potential diagnostic biomarker and as therapeutic targets.

Gene transfer is a widely developed technique for studying and treating genetic diseases. However, the development of therapeutic strategies is challenging, due to the cellular and functional complexity of the central nervous system (CNS), its large size and restricted access. We explored two parameters for improving gene transfer efficacy and capacity for the selective targeting of subpopulations of cells with lentiviral vectors (LVs). We first developed a second-generation LV specifically targeting astrocytes for the efficient expression or silencing of genes of interest, and to better study the importance of cell subpopulations in neurological disorders. We then made use of the retrograde transport properties of a chimeric envelope to target brain circuits affected in CNS diseases and achieve a broad distribution. The combination of retrograde transport and specific tropism displayed by this LV provides opportunities for delivering therapeutic genes to specific cell populations and ensuring high levels of transduction in interconnected brain areas following local administration. This new LV and delivery strategy should be of greater therapeutic benefit and opens up new possibilities for the preclinical development of gene therapy for neurodegenerative diseases.

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology, linked to alterations in both the innate and the adaptive immune system. Due to the heterogeneity of the clinical presentation, the diagnosis of SLE remains complicated and is often made years after the first symptoms manifest, delaying treatment, and worsening the prognosis. Several studies have shown that signaling lymphocytic activation molecule family (SLAMF) receptors are aberrantly expressed and dysfunctional in SLE immune cells, contributing to the altered cellular function observed in these patients. The aim of this study was to determine whether altered co-/expression of SLAMF receptors on peripheral blood mononuclear cells (PBMC) identifies SLE characteristic cell populations. To this end, single cell mass cytometry and bioinformatic analysis were exploited to compare SLE patients to healthy and autoimmune diseases controls. First, the expression of each SLAMF receptor on all PBMC populations was investigated. We observed that SLAMF1+ B cells (referred to as SLEB1) were increased in SLE compared to controls. Furthermore, the frequency of SLAMF4+ monocytes and SLAMF4+ NK were inversely correlated with disease activity, whereas the frequency SLAMF1+ CD4+ TDEM cells were directly correlated with disease activity. Consensus clustering analysis identified two cell clusters that presented significantly increased frequency in SLE compared to controls: switch memory B cells expressing SLAMF1, SLAMF3, SLAMF5, SLAMF6 (referred to as SLESMB) and circulating T follicular helper cells expressing the same SLAMF receptors (referred to as SLEcTFH). Finally, the robustness of the identified cell populations as biomarkers for SLE was evaluated through ROC curve analysis. The combined measurement of SLEcTFH and SLEB1 or SLESMB cells identified SLE patients in 90% of cases. In conclusion, this study identified an immune signature for SLE based on the expression of SLAMF receptors on PBMC, further highlighting the involvement of SLAMF receptors in the pathogenesis of SLE.